FDA panel endorses raloxifene for postmenopausal breast cancer prevention

Postmenopausal women with osteoporosis at high risk for invasive breast cancer.

Issue: September 1, 2007

The FDA’s Oncologic Drug Advisory Committee voted to recommend raloxifene for reducing the risk for invasive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk for breast cancer.

Raloxifene (Evista, Eli Lilly) is indicated to treat osteoporosis in postmenopausal women. The committee voted 8-6 to recommend its approval to reduce breast cancer risk in women with osteoporosis and 10-4 to recommend its approval to reduce the risk in women at high risk. The FDA will make the final regulatory decision, and typically follows a panel’s advice.

The only agent indicated to reduce the risk for breast cancer in women at high risk for the disease is tamoxifen. However, its use is limited due to a high risk profile, including an increased risk for endometrial cancer, according to FDA briefing documents.

In one trial, researchers compared raloxifene with tamoxifen for use in prevention of breast cancer in women at high risk for the disease, and found that raloxifene was associated with a better safety profile than tamoxifen. In a trial of women at risk for major coronary events, however, raloxifene was associated with a higher risk for death from stroke compared with placebo.

“Raloxifene clearly has a benefit, though it is not as great as we would like,” said committee member Michael Perry, MD, director of the division of hematology/medical oncology at the University of Missouri Ellis Fischel Cancer Center in Columbia. “The side effects are more than we would like but are slightly exaggerated and not statistically significant. Overall, raloxifene’s use for prevention is justified.”

Four studies

The committee based its recommendation on four studies of raloxifene. Two studies, Multiple Outcomes of Raloxifene Evaluation (MORE) and Continuing Outcome Relevant to Evista (CORE), evaluated raloxifene in postmenopausal women with osteoporosis.

The MORE study was a double blind, randomized, placebo-controlled, multinational study. It was designed to examine raloxifene’s effect on fracture risk in postmenopausal women with osteoporosis. Women (n=7,705) were randomly assigned to placebo, 60 mg/day of raloxifene or 120 mg/day of raloxifene. Breast cancer was a secondary endpoint.

Compared with placebo, raloxifene showed a 71% decrease (HR=0.29; 95% CI, 0.15-0.56) in the incidence of invasive breast cancer. This benefit was investigated in the CORE study, which was a follow-up evaluation.

In the CORE study, 4,011 of the women from the MORE study continued the blinded treatment after a median gap in therapy of 10.6 months between studies. The primary objective was to evaluate the effect of 60 mg/day of raloxifene vs. placebo on invasive breast cancer incidence. The 60 mg/day dose is the approved dose for osteoporosis prevention.

During the four-year CORE study, raloxifene showed a 56% decrease in the incidence of invasive breast cancer compared with placebo (HR=0.44; 95% CI, 0.24-0.83).

In another study, Raloxifene Use for The Heart (RUTH), researchers analyzed whether raloxifene reduced the risk for acute coronary events or the risk for invasive breast cancer. RUTH was a double blind, multinational, randomized, placebo-controlled study of postmenopausal women at risk for major coronary events.

In RUTH, 10,101 women were randomly assigned to placebo or raloxifene. Raloxifene was associated with a 44% decrease in the incidence of invasive breast cancer (HR=0.56; 95% CI, 0.38-0.83) compared with placebo.

The final study, Study of Tamoxifen and Raloxifene (STAR), compared the effects of raloxifene and tamoxifen on reducing the incidence of invasive breast cancer. Though not placebo-controlled, the foundation of the STAR study was the National Surgical Adjuvant Breast and Bowel Project P-1 study, which compared tamoxifen vs. placebo in women at high risk for invasive breast cancer

For STAR, 19,747 women with a Gail model-based predicted breast cancer risk of 1.66% or more were randomly assigned to tamoxifen or raloxifene. Raloxifene and tamoxifen had similar effects on reducing the incidence of invasive breast cancer.

“Raloxifene is effective at reducing the risk for invasive breast cancer in postmenopausal women with osteoporosis based on the results of three randomized, controlled trials,” said committee member Otis Brawley, MD, professor of hematology/oncology and medicine at the Emory University School of Medicine.

“However, despite the fact that the STAR trial compares tamoxifen and raloxifene, one has to be cautious at comparing the two. There is overwhelming evidence that raloxifene reduces risk compared with placebo, but I do not believe we should be rigorous in comparing raloxifene and tamoxifen,” Brawley said.

Additional considerations

Long-term adverse effects are unknown, and several committee members suggested follow-up trials conducted in a prevention setting to analyze long-term toxicity data, long-term efficacy data and the survival benefit.

The treatments appeared to have no effect on noninvasive breast cancer, which was a concern for several committee members. The committee also expressed a need to set a duration for therapy and to further narrow the scope of patients deemed high risk.

“I see this as a bit of a value added for a patient already being treated with raloxifene for osteoporosis,” said committee member S. Gail Eckhardt, MD, professor of medicine and oncology at the University of Colorado Cancer Center in Aurora. “My concern lies in further narrowing and focusing on the patient population that can clearly benefit in this setting.” – by Emily Shafer

Editor’s note: These studies provide support for a second pharmacological approach for prevention of breast cancer in postmenopausal women at increased risk for breast cancer. As raloxifene is already being used by many older women for osteoporosis management, it is good to know that these women may also enjoy the added benefit of breast cancer risk reduction. With the accumulating evidence it will be important to ensure that high-risk women are identified and counseled about the availability of tamoxifen and raloxifene. Major goals for the future are to refine how we identify the highest-risk women and develop strategies that might be useful for prevention of steroid receptor–negative breast cancer. – Nancy Davidson, MD